Pemetrexed, chemically N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid of formula (I),

is a pharmaceutically active compound used for the treatment of malignant pleural mesothelioma and for second-line treatment of non-small cell lung cancer. The compound has been first disclosed in EP432677.
The disodium heptahydrate salt of pemetrexed is marketed by Eli Lilly under the brand name ALIMTA® and is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The lyophilized product is available in the strengths of 100 mg and 500 mg per vial and is reconstituted with 0.9% saline solution at a concentration of 25 mg/ml. After further dilution with 0.9% saline solution to 100 ml it is then administered intravenously over 10 minutes.
It would be an advantage to have a stable, ready to use reconstituted solution that only has to be further diluted before administration. Particularly with potentially toxic pharmaceuticals like pemetrexed this would be desired, wherein such solution provides easier and safer handling for the caregiver. In addition, it would be particularly desirable if the stable formulation can be prepared without the use of freeze drying techniques.
It is known that a simple, isotonic saline solution of pemetrexed is not pharmaceutically acceptable for commercial purposes due to degradation into unacceptable related substances. The chemical instability of pemetrexed is mainly attributed to oxidative and acidic degradation. According to WO 2012015810, five major degradants of pemetrexed have been detected and identified. Under acidic conditions, decarboxylation of glutamic acid is observed. Under alkaline conditions, degradation proceeds by side chain amide hydrolysis followed by deamination. In the presence of oxygen, two oxidative degradants result.
In literature, several examples are given of stable solutions comprising pemetrexed. WO2012121523 discloses solutions for injection comprising pemetrexed, which are free of antioxidants. WO2013144814 discloses stable ready-to-use pharmaceutical compositions comprising pemetrexed, preferably the disodium salt, wherein the composition is free of antioxidants, amino acids and chelating agents. Both inventions claim that stability of the solutions is achieved by controlling the oxygen content of drug solution and vial headspace. Although in theory degradation could be prevented by controlling the oxygen content, in practice this is not easy to achieve.
WO0156575 discloses pharmaceutical compositions suitable for liquid parenteral administration comprising pemetrexed, preferably the disodium salt, at least one antioxidant, selected from monothioglycerol, L-cysteine and thioglycolic acid, and an excipient. WO2013179248 discloses liquid compositions, comprising pemetrexed, an organic amine, an inert gas and optionally one or more pharmaceutically acceptable excipients. WO2013178214 discloses liquid pharmaceutical solutions comprising pemetrexed, preferably the disodium salt, a solvent and an antioxidant, selected from acetylcysteine and sodium 2-mercaptoethanesulphonate. WO2012015810 discloses liquid compositions comprising pemetrexed, preferably the disodium salt, an antioxidant selected from lipoic acid, dihydrolipoic acid and methionine, a chelating agent selected from lactobionic acid and sodium citrate and a fluid.
Repetition of the examples cited in the prior art show that the long term stability of the disclosed compositions is insufficient. Moreover, some of the compositions are not desirable from a toxicological point of view.
Thus, in view of the prior art cited above, there is still a need for a ready to use reconstituted solution comprising pemetrexed, which is safe and exhibits excellent long term stability.